The relationship between physical function and psychological symptoms in Parkinson's disease: A systematic review and meta‐regression analysis

Abstract Aims This systematic review and meta‐regression aimed to examine available literature reporting measures of physical function, anxiety, and/or depression and whether any relationships exist between these measures in individuals with Parkinson's disease. Methods MEDLINE, CINAHL, AMED, and APA PsychInfo databases were systematically searched. Screening, quality assessment, and data extraction were completed alongside meta‐regression analysis. Results Of 1175 studies retrieved, 40 were selected for analysis with only one study assessing the relationship between physical and psychological outcomes within their cohort. A total of 27 studies were also eligible for meta‐regression analysis—a total sample of 1211 participants. Meta‐regressions of five combinations of paired physical and psychological outcomes showed a significant moderating effect of symptoms of depression (Beck Depression Inventory) on mobility (Timed‐Up‐and‐Go test; coefficient = 0.37, 95% CI 0.09 to 0.65, p = 0.012) and balance (Berg Balance Score) scores (coefficient = −1.25, 95% CI −1.77 to −0.73, p < 0.001). Conclusion Although physical and psychological outcomes of interest were used in all included studies, only one examined their relationship. Our analysis suggests that symptoms of depression may influence measures of mobility and balance. Specifically, as the severity of symptoms of depression increases, performance on measures of mobility and balance worsens.

will exceed 12 million. 4The three main physical symptoms of PD are tremors, muscle stiffness, and slowness of movement. 5In addition, PD can impact an individual's mental well-being, with symptoms of depression, delusions, paranoia, hallucinations, and PD-associated dementia commonplace resulting directly from PD itself or through medication side effects. 6 is well documented that individuals with PD present with higher incidences of mental health (MH) problems such as depression, anxiety, schizophrenia, and psychotic symptoms when compared to the general population. 7,8More specifically, up to 40% of people with PD (PwPD) will have depression 9 or anxiety, 10 whereas this figure is only 17% in the general population. 11Current NICE guidelines 12 do not address or provide specific recommendations for MH problems in this population, instead referring to existing generic guidelines on depression in adults with chronic health problems and how to access allied health professionals (e.g., physiotherapists and PD nurse specialists).This is a striking contrast to other neurological conditions such as multiple sclerosis, where guidelines include specific recommendations for regular cognitive, emotional, or MH screening. 13,14idence in older populations suggests a relationship between physical and psychological presentations. 15There is, however, a paucity of evidence to substantiate such a relationship in the PD population.From available evidence, it has been suggested that PwPD feel that anxiety may amplify their physical symptoms, 16 and when they become more anxious the incidences of freezing of gait increase. 179][20][21] Although these studies show that there might be an association between physical function and psychological symptoms, it is not well understood.It should also be noted that the UPDRS is a global measure of PD severity and includes both motor and non-motor domains.This relationship is yet to be confirmed in more specific measures of physical function such as balance and mobility, or considering other psychological symptoms associated with PD. 22,23 It is our belief that there is likely to be an intrinsic link between physical and psychological symptoms in PD, with the purpose of this review being to investigate this based on work completed to date.
A narrative review published in 2018 suggested the need for further research to better understand the influence of non-motor symptoms on gait and function in PD. 24 To our knowledge, there has been no systematic review of literature reporting outcomes for both physical and psychological measures in individuals with PD.
Given the proportion of individuals with PD impacted by psychological symptoms, future work has the potential to improve the understanding of any interaction between physical and psychological symptoms.
This systematic review and meta-regression analysis aimed to examine available literature reporting outcome measures of physical function, anxiety, and depression; and whether any relationships exist between these measures in individuals with PD.Prior to undertaking this review, it was hypothesized that while many studies commonly collect data for both physical and psychological outcomes in PD research, there will be limited evidence exploring the potential relationship between these outcomes.

| ME THODS
This review was reported following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines 25 and the review protocol was registered on PROSPERO: CRD42021281392.Ethical approval was obtained from York St John University (STHEC0045).

| Searchstrategy
Database searching was undertaken on 10/23/2021.PH independently and systematically searched four databases (MEDLINE, CINAHL, AMED, and APA PsychInfo) from their date of inception until 10/22/2021.A consistent search strategy was used for each database.Table 1 provides details of the search terms used.
Reference lists of all included articles were screened to identify additional studies of interest.

| Inclusionandexclusioncriteria
Following database searching, remaining articles were screened as summarized by the PICOS acronym.Participants: Diagnosis of PD, aged 18 or older.Intervention: Not applicable.Comparison: Not applicable.Outcomes: Inclusion of a physical and psychological outcome measure of interest (see Table 2).Study design: All quantitative study designs are included.Only papers published in peer-reviewed journals and written in English were included, with language screening initially undertaken using automation tools available within the database and subsequently checked manually.
The physical outcome measures of interest were based on the recommendations by the European Physiotherapy Guideline for Parkinson's disease, 26 whereas the psychological outcomes were selected from those used in clinical settings alongside pilot searching of previous work in the area.Physical outcomes include: 10-Minute Walk Test (10 MW) 27 ; 6-Minute Walk Test Distance (6MWT) 28 ; Rapid Turns 29 ; Modified Parkinson Activity Scale (M-PAS) 30 ; Timed-Up-And-Go Test (TUG) 31 ; Push and Release 32 ; Berg Balance Scale (BBS) 33 ; Five times Sit to Stand (FTSTS) 34 ; Dynamic Gait Index (DGI) 35 ; Functional Gait Assessment (FGA) 36 ; and Mini-Balance Evaluation Systems Test (Mini-BEST). 37Psychological outcomes include: Anxiety-Parkinson's Anxiety Scale (PAS) 38 ; Beck Anxiety Inventory (BAI) 39 ; State-Trait Anxiety Inventory (STAI) 40 ; Generalized Anxiety Disorder Assessment (GAD-7) 41 ; Hospital Anxiety and Depression Scale (HADS) 42 ; Depression-Beck Depression Inventory-II (BDI-II) 43 ; Hamilton Depression Rating Scale (HAM-D) 44 ; Geriatric Depression Scale (GDS-15) 45 ; and Hospital Anxiety and Depression Scale (HADS). 42All outcome measures were selected based on existing evidence demonstrating good validity and reliability within the PD population.
Two researchers (PH and AJ) independently screened the titles and abstracts of relevant literature before completing further full-text screening to assess eligibility.Both screening stages were completed using an Excel workbook customized for the review process.Any disagreement was discussed, and if a consensus could not be reached, guidance was available from a third reviewer (CS).
Studies were grouped by outcome and then by outcome pairings for synthesis.All relevant studies identified were included in the systematic review; however, only incidences where five or more studies used the same combination of physical and psychological outcomes were included in the meta-regression analysis.This decision was based on evidence that the 95% confidence interval (CI) included the final estimate in 83% of meta-analyses after five studies. 46integrity.Each domain is scored as strong, moderate, or weak, and studies can be classified as strong, moderate, and weak overall.This tool has appropriate content and construct validity as well as good intra-and inter-rater reliability. 48,49itial training, independent scoring, and consensus discussion for two papers were completed by all assessors prior to full scoring being undertaken.Concurrent and independent quality assessment was performed by two reviewers (PH and AJ).Any disagreements between reviewers were resolved through discussion, with a third reviewer available (CS) when necessary.

| Studyandparticipantcharacteristics
Key study details including title, authors, and year published are summarized in Table 3.This table also includes details of the study population, exclusion criteria, and outcome measures completed within the study.
While all studies included in this review collected data for both physical and psychological outcomes, only one directly investigated the potential relationship between physical (DGI) and psychological (HADS) outcomes collected. 88

| Sample heterogeneity
This table shows all outcome measure combinations identified through article screening.Only combinations used by 5 or more studies are included in the meta-regression.

| DISCUSS ION
To the best of our knowledge, this was the first systematic review and meta-regression analysis to examine available literature reporting outcome measures of physical function, anxiety, and/or depression and whether any relationships exist between these measures in individuals with PD.Despite many studies routinely collecting data for both physical and psychological outcome measures, only one study examined this relationship. 88Our exploratory meta-regression analysis of extracted baseline group-level mean data from previous studies suggests a trend for the physical ability of PwPD to reduce as symptoms of depression increase.
Still et al. 88 completed the only identified study that examined the relationship between physical and psychological outcome measures.Although the authors found significant correlations between participant-reported physical function and anxiety/depression, this was not the case between clinically assessed physical function and anxiety/depression.More specific, significant correlations were found between self-reported motor disability (MDS-UPDRS Part 2) and depression/anxiety (HADS). 88Interestingly, this not only supports the hypothesis of a potential interaction between physical and psychological symptoms in PD but also a potential mismatch in this relationship between participant and clinician physical function assessments.Such discrepancy might be due to how individuals with PwPD perceive physical function in comparison to their clinicians.
Our meta-regression analysis showed that poorer functional ability with gait, balance, and transfers was associated with higher depression scores.Specifically, poorer functional ability with gait and physical capacity (6MWT) were associated with higher depression scores (BDI), while poorer balance (BBS) was associated with higher depression scores (BDI and GDS).Such findings suggest a potential interaction among gait, balance, transfer ability, and physical capacity, with symptoms of depression.The meta-regression  analysis also considered potential moderating effects between outcome measures.Interestingly, a significant moderating effect of depression (BDI) on gait, balance including transfer ability (TUG), and balance (BBS) was found.Our findings suggest that symptoms of depression may directly influence a reduction in physical performance in PwPD evident in outcome measures of gait, balance, and transfer ability.It is possible that such moderating effects may be partially explained by the fact that reduced physical functioning is more likely to increase reliance on others to complete aspects of daily living as the condition progresses. 92However, it is important to note that it is difficult to fully interpret such an effect due to the complexity of such interactions.While the meta-regression analysis conducted as part of this review focuses on the potential influence of psychological distress on physical function, any relationship is likely to be bi-directional in nature and that limited physical function has the potential to further influence psychological symptoms.

TA B L E 5 (Continued)
In comparison with Still et al., the results of our meta-regression analysis suggest that a relationship may exist between clinicianreported physical and participant-reported psychological outcome measures.Such contradictory findings may be due to authors using a combination of outcome measures not encountered in other studies and therefore, unable to include within our metaregression analysis.To add to this, some of the participants in Still et al.'s study reported psychological symptoms mostly classified as "normal to mild," and for this reason, their impact on the clinically reported scales might have been minimal.
Non-motor symptoms including cognitive, mood, autonomic, and sleep disturbances have been observed as a component of PD since its discovery, 93 and previous work has suggested that even at the earliest stages of PD, non-motor symptoms may impair patients' functional status and sense of well-being. 94In addition, those who have been living with PD for longer are more likely to experience a larger number of symptoms, with impairment becoming more pronounced as the disease and its symptoms progress over time. 95spite previous research finding significant correlations between anxiety/depression and changes in gait characteristics, 17,[96][97][98][99] it is yet to translate into evidence of anxiety/depression impacting functional or motor disability assessed through clinical outcome measures recommended by the European Physiotherapy Guideline for Parkinson's Disease. 26r systematic review and meta-regression analysis had several strengths such as the use of multiple reviewers throughout all stages, and the high level of agreement between reviewers due to the comprehensive training prior to appraisal completion.In our review, 77.5% of included studies were rated as either strong or moderate indicating reasonable quality which strengthens our findings.The studies that were rated highly used transparent recruitment methods from multiple sources, fully blinded both participants and assessors to group allocation, and reported withdrawal rates and intervention integrity within their results.This review demonstrates that good-quality data have been collected as part of previous work, which is a source of untapped potential and would serve as a valuable tool in assessing the extent of any relationship between physical function and psychological symptoms in PD, providing evidence to improve clinical service provision.
While we took steps to strengthen this review, some limitations still remain.The inability to access the raw data or correlation coefficients of the included studies despite requesting these from the corresponding authors meant that meta-analysis was not possible, and for this reason, meta-regression analysis of grouplevel mean data was our only option.Although the UPDRS 100 is a commonly used outcome measure, it was not included in the list of outcome measures of interest for two reasons; first, it does not provide the same symptom specificity as the other included outcome measures, and second, it was not listed in the European Physiotherapy Guideline for Parkinson's disease. 26We also chose to focus mainly on psychological measures of anxiety Data extraction was performed by two reviewers (PH and AJ) independently.Discrepancies were resolved through discussion, with a third reviewer (CS) available for consultation if necessary.A standardized pre-piloted Excel spreadsheet was used to extract the following data: lead author; publication date; country; population; study design; intervention type; sample size; age; stage of PD; and details of physical and psychological outcome measures used, including group-level mean and SDs at baseline.It was necessary to extract group-level data as many studies did not report wholesample mean and SD data.Baseline data for each outcome of interest was used to avoid the impact of any study interventions.Authors were contacted in cases of missing or unclear information where required.The Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project (EPHPP) was used to assess the quality of included studies. 47This tool evaluates seven domains: selection bias; study design; confounders; blinding; data collection method; withdrawals and drop-outs; and intervention TA B L E 1 Search terms used and level searched.

Figure 2
Figure 2 displays extracted group mean data.
Physical activity in patients withParkinson's disease: a holistic approach based on the ICF model Aktar B, Balci B, Donmez Colakoglu B A randomized controlled cross-over trial of aerobic training versus Qigong in advanced Parkinson's disease Burini D, Farabollini B, Iacucci S, Rimatori C, Riccardi G, Capecci M, Provinciali L, Ceravolo MG The efficacy of exercise programs for Parkinson's disease: Tai Chi versus combined exercise Cheon SM, Chae BK, Sung HR, Lee GC, Kim JW Multicenter, randomized controlled trial of PDSAFE, a physiotherapistdelivered fall prevention program for people with Parkinson's Chivers Seymour K, Pickering R, Rochester L, Roberts HC, Ballinger C, Hulbert S, Kunkel D, Marian IR, Fitton C, McIntosh E, Goodwin VA, Nieuwboer A, Lamb SE, Ashburn A Effects of a Nordic Walking program on motor and non-motor symptoms, functional performance and body composition in patients with Parkinson's disease Cugusi Lucia, Solla Paolo, Serpe R, Carzedda T, Piras Luisa, Oggianu M, Gabba S, Di Blasio A, Bergamin M, Cannas A, Marrosu F, Mercuro G Effects of an adapted physical activity program on motor and non-motor functions and quality of life in patients with Parkinson's disease Cugusi L, Solla P, Zedda F, Loi M, Serpe R, Cannas A, Marrousa F, Mercuro G The effects of arm crank training on aerobic capacity, physical performance, quality of life, and health-related disability in patients with Parkinson's disease Dağ F, Çimen ÖB, Doğu O Resistance training reduces depressive symptoms in elderly people with Parkinson's disease: a controlled randomized study de Lima TA, Ferreira-Moraes R, Alves WMGDC, Alves TGG, Pimentel CP, Sousa EC, Abrahin O, Cortinhas-Alves EA Predictors of physical activity levels in individuals with Parkinson's disease: a cross-sectional study.Feliciano JS, Rodrigues SMA, de Carvalho Lana R, Polese, JC The effects of functional training, bicycle exercise, and exergaming on walking capacity of elderly patients with Parkinson's disease: a pilot randomized controlled single-blinded trial Ferraz DD, Trippo KV, Duarte GP, Neto MG, Bernardes Santos KO, Filho JO KICK OUT PD: feasibility and quality of life in the pilot karate intervention to change kinematic outcomes in Parkinson's disease Fleisher JE, Sennott BJ, Myrick E, Niemet CJ, Lee M, Sanghvi M, Liu Y, Ouyang B, Hall DA, Comella CL, Chodosh J Effectiveness of a dance-physiotherapy combined intervention in Parkinson's disease: a randomized controlled pilot trial Frisaldi Elisa, Bottino P, Fabbri M, Trucco M, De Ceglia A, Esposito N, Barbiani D, Camerone EM, Costa F, Destefanis C, Milano E, Massazza G, Zibetti M, Lopiano L, Benedetti F Body awareness training in the treatment of wearing-off related anxiety in patients with Parkinson's disease: results from a pilot randomized controlled trial Ghielen I, van Wegen EEH, Rutten S, de Goede CJT, Houniet-de Gier M, Collette EH, Burgers-Bots IAL, Twisk JWR, Kwakkel G, Vermunt K, van Vliet B, Berendse HW, van den Heuvel OA Nordic Walking and walking in Parkinson's disease: a randomized singleblind controlled trial Granziera S, Alessandri A, Lazzaro A, Zara D, Scarpa A Functional outcomes of an integrated Parkinson's disease well-being program Horne JT, Soh D, Cordato DJ, Campbell ML, Schwartz RS Exercise management using a mobile app in patients with Parkinsonism: prospective, open-label, single-arm pilot study Kim A, Yun SJ, Sung K-S, Kim Y, Jo JY, Cho H, Park K, Oh B-M, Seo HG Effects of group, individual, and home exercise in persons with Parkinson's disease: a randomized clinical trial King LA, Wilhelm J, Chen Y, Blehm R, Nutt J, Chen Z, Serdar A, Horak FB Turo (Qi Dance) program for Parkinson's disease patients: randomized, assessor blind, waiting-list control, and partial crossover study Lee HJ, Kim SY, Chae Y, Kim MY, Yin C, Jung WS, Cho KH, Kim SN, Park HJ, Lee H A structural model of health-related quality of life in Parkinson's disease patients Lee J, Choi M, Jung D, Sohn YH, Hong J Impacts of an exercise program and motivational telephone counseling on health-related quality of life in people with Parkinson's disease Lee J, Choi M, Yoo Y, Ahn S, Jeon JY, Kim JY, Byun JY Neural networks associated with quality of life in patients with Parkinson's disease Nakano T, Kajiyama Y, Revankar GS, Hashimoto R, Watanabe Y, Kishima H, Ikeda M, Mihara M, Mochizuki H, Hattori N Health-related quality of life and physical function in individuals with Parkinson's disease after a multidisciplinary rehabilitation regimen-a prospective cohort feasibility study Nielsen C, Siersma V, Ghaziani E, Beyer N, Magnusson SP, Couppé C Effects of robotic treadmill training on functional mobility, walking capacity, motor symptoms, and quality of life in ambulatory patients with Parkinson's disease: a preliminary prospective longitudinal study Paker N, Bugdayci D, Goksenoglu G, Sen A, Kesiktas N DRUM-PD: the use of a drum circle to improve the symptoms and signs of Parkinson's disease (PD) Pantelyat A, Syres C, Reichwein S, Willis A Nordic walking and free walking improve the quality of life, cognitive function, and depressive symptoms in individuals with Parkinson's disease: a randomized clinical trial Passos-Monteiro E, B Schuch F, T Franzoni L, R Carvalho A, A Gomeñuka N, Becker M, Rieder CRM, Andrade A, G Martinez F, S Pagnussat A, A Peyré-Tartaruga L Tango for treatment of motor and non-motor manifestations in Parkinson's disease: a randomized control study Rios Romenets S, Anang J, Fereshtehnejad S-M, Pelletier A, Postuma R Exercise increases caudate dopamine release and ventral striatal activation in Parkinson's disease Sacheli MA, Neva JL, Lakhani B, Murray, Danielle K, Vafai N, Shahinfard E, English C, McCormick S, Dinelle K, Neilson N, McKenzie Jessamyn, Schulzer Michael, McKenzie DC, Appel-Cresswell S, McKeown MJ, Boyd LA, Sossi V, Stoessl AJ Sardinian folk dance for individuals with Parkinson's disease: a randomized controlled pilot trial Solla P, Cugusi L, Bertoli M, Cereatti A, Della Croce U, Pani D, Fadda L, Cannas A, Marrosu F, Defazio G, Mercuro G The effects of mindfulness meditation-based complex exercise program on motor and nonmotor symptoms and quality of life in patients with Parkinson's disease Son HG, Choi E-O Self-reported depression and anxiety are correlated with functional disability in Parkinson's disease Still A, Hale L, Swain N, Jayakaran P Vastly different exercise programs similarly improve Parkinsonian symptoms: a randomized clinical trial Tollár J, Nagy F, Hortobágyi T A high-intensity multicomponent agility intervention improves Parkinson patients' clinical and motor symptoms Tollár J, Nagy F, Kovács N, Hortobágyi T A pilot study to evaluate multidimensional effects of dance for people with Parkinson's disease Ventura MI, Barnes DE, Ross JM, Lanni KE, Sigvardt KA, Disbrow EA Dance for PD: a preliminary investigation of effects on motor function and quality of life among persons with Parkinson's disease (PD) Westheimer O, McRae C, Henchcliffe C, Fesharaki A, Glazman S, Ene H, Bodis-Wollner I Effect of simplified Tai Chi exercise on relieving symptoms of patients with mild-to-moderate Parkinson's disease Zhu M, Zhang Y, Pan J, Fu C, Wang Y Short-term effectiveness of intensive multidisciplinary rehabilitation for people with Parkinson's disease and their carers Trend P, Kaye J, Gage H, Owen C, Wade D Habitual exercisers versus sedentary subjects with Parkinson's disease: multimodal PET and fMRI study Sacheli MA, Murray DK, Vafai N, Cherkasova MV, Dinelle K, Shahinfard E, Neilson N, McKenzie J, Schulzer M, Appel-Cresswell S, McKeown MJ, Sossi V, Jon Stoessl A Wii Fit balance board playing improves balance and gait in Parkinson's disease Mhatre PV, Vilares I, Stibb SM, Albert MV, Pickering L, Marciniak CM, Kording K, Toledo S Effect of virtual reality dance exercise on the balance, activities of daily living, and depressive disorder status of Parkinson's disease patients Lee NY, Lee DK, Song HS Gait velocity and step length at baseline predict outcome of Nordic walking training in patients with Parkinson's disease Herfurth M, Godau J, Kattner B, Rombach S, Grau S, Maetzler W, Berg D Note: Key: Green = Strong; Orange = Moderate; Red = Weak.Blue colour used to indicate no scoring related to this column.

F I G U R E 2
Relationship between physical and psychological outcomes.Top left: 6MWT plotted against BDI.Trendline showing BDI score increases as 6MWT distances reduces.Supports hypothesis of increased level of depression with worsening physical function.Middle left: TUG plotted against BDI.Trendline showing BDI score increases as TUG increases.Supports hypothesis of increased level of depression with worsening physical function.Bottom left: BBS plotted against BDI.Trendline showing BDI score increases as BBS reduces.Supports hypothesis of increased level of depression with worsening physical function.Top right: TUG plotted against GDS.Trendline showing GDS score increases as TUG increases.Supports hypothesis of increased level of depression with worsening physical function.Middle right: BBS plotted against GDS.Trendline showing GDS score increases as BBS reduces.Supports hypothesis of increased level of depression with worsening physical function.
51,74 reported, the mean group age of participants ranged from 58.23 years 56 to 72.38 years.59Allstudiesonlyincluded PwPD, with only two studies51,74allocating to including participants at stage IV.